Mikrokristalline Cellulose II (English shop)

Eignung als Pelletierhilfsstoff bei der Feuchtextrusion/Sphäronisation zur Herstellung zerfallender Pellets

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Microcrystalline cellulose I is a widely used pharmaceutical excipient in pelletisation by wet extrusion/spheronisation as well as in tabletting. Its polymorph MCC II, which exhibits a different structure in the crystalline regions, has only recently become commercially available. Previous investigations on tablets demonstrated its superior disintegration behaviour compared with MCC I-based products. Using MCC II as a pelletisation aid, it was possible for the first time in the framework of this study to produce rapidly disintegrating cellulose-based pellets by wet extrusion/spheronisation, whereby water was used as the granulation liquid and no addition of binders or disintegrants was necessary. The production of pellets from MCC II was possible with various active ingredients and excipients at a loading of 80% (m/m). All formulations disintegrated within 5 min in water. Furthermore, lower drug loadings of 50% to 70% (m/m) could be realised, as well as the production of pellets consisting of 100% MCC II. Drug loadings of 90% were also possible, but resulted in a more difficult process control. With increasing MCC II content, the pellets became larger, their porosity decreased and more water was required for their production. In addition, the disintegration time increased and disintegration became less complete. In some cases, the formulations with a 90% drug content represented exceptions to this rule, as they exhibited a longer disintegration time than the formulations with 80% drug loading. Besides the disintegration properties, MCC II-based pellets also differed from MCC I-based pellets in many other aspects: the acceptable moisture range was narrower for the MCC II-based pellets, but they required less water during production. Moreover, the MCC I-based pellets were superior with regard to their pellet shape and crushing strength. Pellets made from MCC II had a larger equivalent diameter as well as a higher porosity. Due to their disintegration, the MCC II-based pellets showed no matrix release; they released their drug rapidly in comparison with the MCC I-based pellets. A further difference could be determined in the spheronisation mechanisms of the two pelletisation aids: the spheronisation mechanism of the MCC II-based formulations differed from the known mechanisms. In previous models, the plastic deformation of the extrudate fragments was of prime importance. In the case of the pellets made from MCC II, plastic deformation also occurred during spheronisation, but pellet attrition and subsequent deposition of the powder as well as an interparticulate mass exchange between the pellets were decisive for the rounding of the pellets. As a result of this mechanism, an increase in pellet mass as well as a narrower pellet size distribution occurred during spheronisation. In contrast, no increase in mass during spheronisation was observed for the MCC I-based pellets. For MCC II-based pellets an optimal spheronisation time of 8 min could be determined. Pellet size and pellet shape could be influenced via spheronisation time and spheronisation speed. The influence of the spheroniser load on pellet quality, by contrast, was negligible. In a further part of the work, the disintegration properties of MCC II-based preparations were investigated in more detail. In the MCC II-based pellets, the disintegration properties were irreversibly lost after storage at high relative humidities ((80% RH–)97% RH), whereby drug release was slowed down. Thus, only storage below 80% RH could ensure that no changes in disintegration behaviour occurred. If theophylline monohydrate was used as the active ingredient in MCC II-based pellets, storage had to take place between 55% RH and 80% RH (20 °C). Only within this humidity range did the disintegration and release properties of the pellets remain unchanged. At relative humidities below 55% RH, theophylline anhydrate was formed, which developed a network around the pellet and thereby prevented pellet disintegration. A comparative system of tablets could be established alongside the pellets: tablets made from extruded MCC II granules behaved similarly to the MCC II-based pellets. Their disintegration behaviour was likewise irreversibly altered by storage at high humidity, and in addition the disintegration time was prolonged with increased MCC II content. Tablets made from MCC II powder behaved differently: the changes caused by the high storage humidities were reversible, and with increasing MCC II content in the tablets an accelerated disintegration occurred. Granulation moreover strongly increased the crushing strength of the tablets, slowed down disintegration and improved drug distribution. Furthermore, the disintegration mechanisms of the tablets differed: the disintegration of tablets made from MCC II granules was brought about by swelling, whereas in the tablets made from MCC II powder a wicking effect appeared to be responsible for disintegration. An enlargement of the surface area and a reduction in particle size of the MCC II caused by extrusion was regarded as one reason for the differences between the tablets made from MCC II powder and the pellets or tablets made from granules. As a result, interactions between the MCC II molecules could occur to a greater extent, as described in the crystallite-gel model of Kleinebudde. Overall, it was possible to explain many properties of the tablets made from granules and of the pellets on the basis of this model. MCC II is a new pelletisation aid which, owing to its disintegration-promoting property, represents an excellent complement to the standard pelletisation aid MCC I. A general contribution could be made both to the understanding of the disintegration behaviour of MCC II-based dosage forms and to the investigation of disintegration properties. In addition, the rounding mechanism of MCC II-based pellets could be elucidated.